Substituted phenylacetic acids and esters thereof

ABSTRACT

Substituted phenyl acetic acids, addition salts thereof with bases as well as esters thereof, which compounds exhibit useful antiinflammatory (antiphlogistic), analgesic and antipyretic activity, and processes for the production of these compounds, as well as starting materials used in said processes; therapeutic compositions containing these compounds, and methods of treatment, particularly methods of inducing antiinflammatory, analgesic and antipyretic effects in mammals. Illustrative embodiments are 2-(p-(1-pyrryl)-phenyl)-butyric acid, (3-chloro4-(1-pyrryl)-phenyl)-acetic acid and 2-(p-(1-pyrryl)-phenyl)propionic acid methyl ester.

[ 1 June 27, 1972 SUBSTITUTED PHENYLACETIC ACIDS AND ESTERS THEREOFInventors: Rolf Denss, Basel, Switzerland; Niels Clauson-Kaas, Farum,Denmark; Franz Ostermayer, Riehen, Switzerland Assignee: Geigy ChemicalCorporation, Ardsley,

Filed: April 29, 1970 Appl. No.: 43,637

Related US. Application Data Division of Ser. No. 679,224, Oct. 30,1967, Pat. No. 3,579,535.

Foreign Application Priority Data [56] References Cited UNITED STATESPATENTS 3,151,121 9/1964 Karmas et al. ..260/326.3 X

Primary Examiner-Alex Mazel Assistant Examiner-Joseph A. NarcavageAttorney-Karl F. .lorda and Martin J. Spellman ABSIRACT Substitutedphenyl acetic acids, addition salts thereof with bases as well as estersthereof, which compounds exhibit useful antiinfiammatory(antiphlogistic), analgesic and antipyretic activity, and processes forthe production of these compounds, as well as starting materials used insaid processes; therapeutic compositions containing these compounds, andmethods of treatment, particularly methods of inducing antiinflammatory,analgesic and antipyretic effects in mammals. Illustrative embodimentsare 2-[p-( l-pynyl)-phenyl]-butyric acid, [3-chloro-4-(l-pyrryl)-phenyl]-acetic acid and 2-[p-( l-pynyl)-phenyl]-propionic acidmethyl ester.

4 Claims, No Drawings SUBSTITUTED PHENYL'ACETIC ACIDS AND ESTERS THEREOFThis application is a division of application Ser. No. 679,224, filedOct. 30, 1967, now US. Pat. No. 3,579,535.

DETAILED DISCLOSURE The invention relates to substituted phenyl aceticacids, to addition salts thereof with inorganic or organic bases, aswell as to esters thereof, which compounds exhibit valuablepharmacological properties. It further pertains to processes for theproduction of these compounds and is also concerned with startingmaterials used in said processes. It is further an object of theinvention to provide therapeutic compositions consisting essentially ofl) a substituted phenyl acetic acid according to the invention, or anester thereof, or a pharmaceutically acceptable addition salt thereofwith an inorganic or organic base, and (2) a pharmaceutical carrier.Another object of the invention is to provide methods of treatmentinvolving the administration to a mammal requiring such treatment of apharmacologically effective amount of a substituted phenyl acetic acidaccording to the invention, or an ester thereof, or a pharmaceuticallyacceptable addition salt thereof with an inorganic or organic base; themethods of treatment according to this invention comprise particularly amethod of producing an antiinflammatory (antiphlogistic) effect, amethod of producing an analgesic effect as well as a method of producingan antipyretic effect.

Substituted phenyl acetic acids and esters thereof corresponding to theformula I Ra R2 wherein R represents hydrogen, lower alkyl, loweralkenyl or lower alkynyl, 7

R represents hydrogen, lower alkyl, lower alkoxy or halogen, and

R R, and R independently of each other represent hydrogen or loweralkyl, as well as the addition salts of the carboxylic acids having theformula I with inorganic or organic bases, have not been described up tonow. 7

In the compounds of formula I and the related starting materialsmentioned hereinafter, R as a lower alkyl group is, e.g., the methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, n-pentyl,isopentyl, neopenty], n-hexyl or isohexyl group; as a lower alkenylgroup is, e.g., the allyl, 2-methylalkyl or crotyl group; and as a loweralkynyl group is, e.g., the 2propynyl, Z-butynyl or 3-butynyl group. R,as a lower alkyl group which is also occuring in a lower alkoxy group Ris, e.g., the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ortert. butyl group and as halogen atom, e.g., chlorine, bromine orfluorine. Lower alkyl groups R and R are, e.g., methyl, ethyl, n-propylor isopropyl groups. The lower alkyl group R is, e.g., the methyl,ethyl, rl-propyl, isopropyl, n-butyl, isobutyl, tert. butyl, n-pentyl,isopentyl or n-hexyl group.

If not otherwise defined the terms low alkyl or lower alkyl as usedherein per se and as included in the terms low alkoxy or lower alkoxy,"respectively, mean saturated monovalent aliphatic groups of the generalformula --C,,,H m l wherein m designates an integer of less than 7 andare inclusive for both straight and branched chain-groups, whereas theterms low alkanol or lower alkanol" mean compounds of the generalformula C,,,H ,,,,,-OH, the definition of the C,,,H,,,, moiety of whichcorresponds to that given above for low alkyl or lower alkyl,respectively.

For the production of compounds of the formula I and salts of thecarboxylic acids having this formula with inorganic or organic bases,according to the invention a compound of the formula II Ha a.

R xii-0- wherein at most two Rs in each unit represent low alkyl groupsand the rest represent hydrogen atoms,

X and X independently of each other represent radicals of the formulas RO- and R -CO0, wherein R represents an optionally halogen-substitutedhydrocarbon radical or chlorine or bromine atoms, or X together with Yis also the Oxo radical =0,

Y and Y independently of each other represent radicals of theabove-defined formulas R -0 or R,,COO- or both together the epoxyradical O-, or each together with Z or Z, respectively, represents anextra bond corresponding. to the dotted lines, and

Z and Z represent hydrogen atoms, provided they do not have the abovegiven meaning, and

n represents 0 or a low whole number, or with a mixture of suchsubstances while heating in the presence or absence of a diluent and/orcondensing agent, and if desired a free carboxylic acid of the generalformula I so obtained is converted into a salt with an inorganic ororganic base.

As examples of 'y-dioxo compounds usable according to the inventionsuccinicaldehyde, Z-methyIsuccinicaldehyde, 2,3-dimethyl-succinicaldehyde, levulinic aldehyde, 4-oxohexaldehyde and2,5-hexanedione can be mentioned.

Of the compounds of general formula III which can be used instead of themonomeric or polymeric, saturated aliphatic 'ydioxo compounds with atmost 10 carbon atoms, the following are mentioned as examples ofopen-chain derivatives of monomeric succinicaldehyde: acetals such assuccinic aldehyde monodiethyl acetal, succinic aldehyde bis-dimentylacetal, succinic aldehyde bis-diethyl acetal; acylals such as succinicaldehyde- 1 l-diacetate (4,4-diacetoxy-butyraldehyde); enol ethers suchas 1,4-diphenoxy-butadiene; enol esters such as 1,4-diacetoxy-butadiene.Compounds of the general formula III in which Y and Y together form theepoxy radical are tetrahydrofuran derivatives which react in the sameway as the acetals or acylals of succinic aldehyde and other -y-dioxocompounds as defined or as the open chain ahalogen ethers, depending onthe meaning of X and X. Such compounds are, for example, the following,optionally substituted by low alkyl groups: 2,5-dialkoxy-tetrahydrofuranand related compounds, such as 2,5-dimethoxy-tetrahydrofuran,2,5-diethoxy-tetrahydrofuran, 2,5'dipropoxy-tetrahydrofuran,2,5-dimethoxy-tetrahydrofuran, 2,S-bisallyloxy-tetrahydrofuran,2,5-bis-(2-chloroethoxy)-tetrahydrofuran, 2,5-diphenoxy-tetrahydrofuranand 2,5-bis-(3,4-xylyloxy)-tetrahydrofuran,2-methyl-2,5-dirnethoxy-tetrahydrofuran and 3-methyl-2,5-dimethoxy-tetrahydrofuran, furthermore 2,5-diacyloxytetrahydrofurans,such as 2,5-diacetoxy-tetrahydrofuran, as well as2,5-dihalo-tetrahydrofurans, such as 2,5-dichlorotetrahydrofuran and2,5-dibromo-tetrahydrofuran and, finally, also compounds which areregarded as two types simultaneously such as2-chloro-5-(2-chloroethoxy)- tetrahydrofuran and2-allyloxy-5-chloro-tetrahydrofuran.

Compounds of the general formula III in which n is l or higher than 1and, particularly mixtures of such compounds wherein n is different, areformed, e. g., on treating polymeric succinic aldehyde with amounts ofacetalizing or acylating substances or mixtures of substances which areless than equivalent to the succinic aldehyde units present.

A suitable medium for the reaction according to the invention when afree 'y-dioxo compound is used, is any solvent in which the 'y-diOXOcompound is soluble, for example, methanol, ethanol or acetic acid.Acetals and acylals of the -ydioxo compounds as well as cyclic,acetyl-like derivatives are advantageously reacted in acetic acid assolvent and condensing agent, or in the presence of catalytic amounts ofan acid condensing agent, such as p-toluene sulphonic acid, in thepresence or absence of an inert organic solvent or diluent such asbenzene, toluene, o-dichlorobenzene or acetonitrile. The reaction ofcompounds of the general formula III wherein X and/or X are halogenatoms is performed, e.g., in inert organic solvents such as chloroformor those given above. The reaction temperature lies preferably betweenroom temperature and the boiling temperature of the solvent or diluentused, the lower limit being used in particular for the halogen compoundslast mentioned above.

Several compounds of the general formula II, such as(paminophenyl)-acetic acid and p-amino-hydrotropic acid as well as somelower alkyl esters of both acids, 2-(p-aminophenyl)-butyric acid and2-(p-aminophenyl)-valeric acid are known. Further compounds of thegeneral formula II can be produced analogously to the known compounds orby other processes which are known per se.

According to a second process related to that above, compounds ofthegeneral formula I and salts of the carboxylic acids having thisformula, are obtained by heating a mixture of a compound of the generalformula II or a salt thereof with an acid of the formula IV particularlywith mucic acid or saccharic acid unit substantially four times themolar amount of water and double the molar amount of carbon dioxide aresplit off, and if desired converting the thus obtained free carboxylicacid having the general formula I into a salt with an inorganic ororganic base. The reaction according to the aspect of the invention ispreferably performed at temperatures between 100 and 300 in the presenceor absence of inert organic solvents having a medium or high boilingpoint or range such as xylenes, xylene mixtures or diethylene glycoldimethyl ether. The reaction may be performed in one step or in twoseparate steps in that, after heating, an intermediate correspondingp-(Z-carboxyl-l-pyrryl) compound is isolated as main product or as aside product, when the reaction is partially taken to completion, and isthen decarboxylated by further heating as necessary. Mucic acid orsaccharic acid salts of compounds of the general formula II can also beconverted by dry distillation or sublimation into correspondingcompounds of the general formula I. The dry-distillation or sublimationis conducted at reduced pressure so that suitable reaction temperaturemay be used.

ln a third process compounds of the general formula I and salts of thecarboxylic acids having this formula are obtained by heating a compoundof the general formula V tures, e.g., between 170 230, preferably atabout 200". It can be performed in the absence of solvent or diluents,or optionally with such agents, e.g., high boiling tertiary heterocyclicbases such as collidine or chinoline together with copper oxide orcopper powder as catalyst.

Starting materials of the general formula V are obtained for example bycondensing compounds of the general formula II, defined above, withlower 2,5dialkoxy-tetrahydro-2-furancarboxylic acid alkyl esters, whichare optionally substituted according to the definition for R and R inpositions 3', 4 or 5 analogous to the first mentioned process ofproducing compounds of the general formula I, by subsequentlyhydrolyzing the so obtained l-[p-(l-carboxymethyl)-phenyl]-pyrrol-2-carboxylic acid alkyl esters orl[p-(l-alkoxycarbonyl-methyl)- phenyl]-pyrrol-2-carboxylic acid alkylesters, which are optionally substituted according to the definition forR R R and R In the second given process it has already been mentionedthat on reacting compounds of the general formula ll with mucic acid orsaccharic acid optionally (p-2-carboxyllpyrryl) compounds may beisolated as intermediate products. Such products are also startingmaterials of the general formula V, wherein R and R, are always hydrogenatoms. The above mentioned second reaction step of the second givenprocesscorresponds to the instant third given process of producingcompounds of the general formula I.

According to a fourth process compounds of the general formula I inwhich R represents a low alkyl, low alkenyl or low alkynyl group, areproduced by reacting a compound of the general formula Ia which fallswithin the scope of the formula I and in which R R R and R have the samemeanings as given in Formula I, in the presence of substantially doublethe molar amount or equimolar amount of an alkaline condensing agent,according to whether R is hydrogen or a low alkyl group, whichsubstantially equimolar amount of a reactive ester of a hydroxy compoundof the general formula VI R, OH v1 in which R, has the same meaning asR, in formula I with the exception of hydrogen, i.e., it stands for alow alkyl, low alkenyl or low alkynyl group, and when an alkali salt ofa carboxylic acid of general formula I is obtained, optionallyliberating the free acid and, if desired, again converting it into asalt with an inorganic or organic base. By substantially double molar orequimolar amounts of alkaline condensing agent or equimolar amounts ofreactive esters are understood such amounts which, in consideration ofthe availability of the starting materials of the general formula Ia aswell as the possibility of separating the desired monoalkylation productfrom the starting material on the one hand and from any resultingdialkylation product on the other hand, give the best possible yield ofpure end product. In practice, approximately 1.8-2.6 or 0.9 1.3 timesthe molar amount of condensing agent, or 0.6 1.5 times the molar amountof reactive ester, calculated on the starting material of the generalformula la, is used. Suitable alkaline condensing agents are for examplealkali metal amides and alkali metals, particularly sodium amide orsodium, in liquid ammonia as reaction medium at reaction temperatures offrom about to room temperature, preferably at about 50 to 30. Thestarting materials of the general formula la can be obtained, forexample, according to the first mentioned process for the production ofcompounds of the general formula l as well as according to processesmentioned further below. Suitable reactive esters of hydroxy compoundsof general formula VI, i.e., of low alkanols, alkenols and alkynols are,for example, halides such as bromide, iodide and chloride, alsosulphonic acid esters, such as methane sulphonic acid ester andp-toluene sulphonic acid ester, as well as dimethyl sulphate and diethylsulphate.

According to a fifth process compounds of the general formula I and thesalts of the free acids having this general formula are obtained byreacting a compound of the general formula VII wherein A represents alow alkoxy-carbonyl group (CO-O-a1- kyl) or the cyano group,particularly lower alkoxy carbonyl, and A represents a loweralkoxy-carbonyl group, a lower alkoxalyl group (-COCOO-alkyl), the cyanogroup or the acetyl group, particularly lower alkoxy-carbonyl, and

R R R and R have the meanings given under formula I,

with an alkali hydroxide in an organic, organic-aqueous or aqueousmedium, or, if neither A, nor A is a cyano group, reacting with analkalialkanolate in anhydrous medium, or if A is not an acetyl group,reacting with an aqueous mineral acid, liberating the free acid from thealkali salt of a dicarboxylic acid or a dicarboxylic monoalkylesterobtained when an alkali hydroxide is used, and heating until theequimolar amount of carbon dioxide and, as the case may be, carbonmonoxide is split off and if desired converting a so-obtained freecarboxylic acid into a salt with an inorganic or organic base.

The reactions with alkali hydroxides, especially sodium or potassiumhydroxide are preferably performed while heating. Examples of suitablereaction medium are, e.g., lower al-' kanols, such as methanol, ethanol,isopropanol or n-butanol, also an alkandiole or a monoalkyl etherthereof, e.g., ethyleneglycol, 2-methoxy-ethanol or 2-ethoxyethanol,adding, as the case may be, water to the said solvents in a volume ratiofrom about I021 to 1:2. Furthermore water or, e.g., a mixture of waterand water soluble etheric solvents, such as dioxan or tetrahydrofurancan be used.

On reacting malonic acid dialkylesters, acetacetic acid alkylesters oralkoxalylacetic acid alkylesters with alkali-alkanolates preferably thesame lower alkanol, such as methanol, ethanol, n-butanol as a componentof the starting esters and of the alkanolates, as well as the reactionmedium is present. An alcoholysis can however also be carried out usingas reaction medium a relatively high boiling alkanol which is notidentical to the lower alkanol present as ester component and distillingoff a part thereof together with the reaction according to thedefinition. If the esters of the general formula I, obtained as reactionproduct, are not used directly as active substance but are to behydrolyzed to the corresponding acid a partial alcoholysis may beperformed. Furthermore as reaction medium instead of lower alkanol maybe used, e.g., an inert organic solvent such as benzene or toluene. Thereaction according to the definition is performed at room temperature orelevated temperature, e.g., at boiling temperature of the reactionmedium used.

While in the prior mentioned process salts or esters of monocarboxylicacids of the general formula I are obtained during the reaction withalkaline hydroxides under vigorous reaction conditions, e.g., in aboiling mixture of ethyleneglycol with little water, under milderconditions, e.g., in water or in lower alkanols first salts ofdicarboxylic acids are obtained, or if a dicarboxylic acid dialkylesterhaving the general formula VII is reacted with only the equimolar amountof alkalihydroxide the salts of the monoalkyl esters of the carboxylicacids are obtained. From these according to the process thecorresponding dicarboxylic acids or dicarboxylic acid monoalkyl estersof the formula Vlla wherein m represents 0 or 1, and

R R R R and R have the meanings given in formula I, are liberated andthen decomposed to compounds of the general formula I. The compounds ofthe general formula VIIa as intermediate products are produced not onlyaccording to the above process from compounds of the general formula VIIbut also by other means. For example dicarboxylic acids of the generalformula VIIa are produced by hydrolyzing the correspondingdibenzylesters as well as by mild acid hydrolysis of ditert. butylesters, while dicarboxylic-mono alkyl esters of the general formula VIIacan be produced, e.g., by hydrogenolyzing corresponding benzyl alkylesters or also by hydrolyzing corresponding dialkylesters under mildconditions, e.g., with an equimolar amount of an alkali acetate in thelower alkanol corresponding to the group R Furthermore alkali salts ofdicarboxylic acids of the general formula VIla are produced analogouslyto a process mentioned below for the production of carboxylic acids oralkali salts thereof falling under the general formula I by reactinginstead of optionally the lower (p-sulfinylimino phenyl)acetic acidalkyl esters of the general formula XIII which are substitutedcorresponding to the definition for R and R the corresponding lower(p-sulfinylimino-phenyl)-malonic acid dialkyl esters, lower(p-sulfinylimino)-oxalic acetic acid dialkyl esters or lower(p-sulfinylimino)-cyanic acetic acid alkyl esters with butadiene oralkyl substituted butadiene of the general formula XIV and by reactingthe addition products analogously to the compounds of the generalformula XV with alkali hydroxydes, especially in organic oraqueous'organic medium while heating.

The process defined further above comprises therefore also an embodimentaccording to which a compound of the general formula VIIa produced froma compound of the general formula VII or by other means, wherein m, R,,R R R and R have the meaning given therein or under formula I is heatedin presence or absence of a catalyst and a solvent or a diluent untilthe equimolar amount of carbon dioxide and, in such a case, carbonmonoxide is split off, and if desired obtained free carboxylic acid isconverted into a salt with an inorganic or organic base.

Starting materials of the general formula VII are produced starting fromlower [p-( l-pyrryl)-phenyl]-acetic acid alkyl esters which aresubstituted according to the definition for R R and R and correspond tothe general formula Ia or from optionally correspondingly substituted[p-(1-pyrry)-phenyl]- acetonitrile which may be obtained analogously tothe first mentioned production process from corresponding (p-aminophenyl)-acetonitriles. The mentioned alkylesters or nitriles arecondensed with the aid of alkali metal alkanolates with lowerdialkylcarbonates, lower oxalic acid alkyl esters or lower acetic acidalkyl esters yielding compounds of the general formula VII with ahydrogen atom as radical R,. The

alkali metal compounds of these intermediate products are reacted withreactive esters of hydroxyl compounds of the general formula VI tocompounds of the general formula VII with a radical R other thanhydrogen. The sequence of the different operations which finally lead tocompounds or the general formula VII may be varied in various ways, e.g., starting from p-nitrophenyl malonic acid dialkyl esters orpnitrophenyl cyano acetic acid alkyl esters, first reducing these to thecorresponding p-aminophenyl compounds and then closing the ring of thelatter to the corresponding p-( l-pyrryl)- phenyl compounds. Furthermoresubstituted cyano acetic acid alkyl esters may be converted intocorrespondingly substituted malonic acid dialkyl esters in differentwell known reaction stops, e.g., by reacting with hydrogen chloride andwith an aqueous lower alkanol. As (p-nitrophenyl)-cyano acetic acid(lower)-alkyl esters may be produced not only from corresponding(p-nitrophenyl)acetic acid (lower)alkyl esters or(p-nitrophenyl)-acetonitriles, that means not only from compounds fromwhich end products of the general formula I with a hydrogen atom as Rare accessible in the shortest way, but also by condensingp-nitrochlorobenzene with cyano acetic acid alkyl esters, the finaltransformation of compounds of the formula VII into those of the generalformula I is also of practical importance, when in the mentionedcompounds R is represented by hydrogen. Finally, starting materials ofthe general formula VII can be produced in situ, that means immediatelybefore being directly split according to the invention by means ofalkali hydroxides to alkali salts of car boxylic acids of the generalformula I, in the same working operation from the partly alreadymentioned addition products which are analogous to the compounds of thegeneral formula XV, of (p-sulfinyliminophenyl)-malonic aciddi(lower)alkyl esters, (p-sulfinyliminophenyl)-oxalic acetic aciddi(lower)alkyl esters, (p-sulfinyliminophenyl)-cyano acetic acid(lower)alkylesters and (p-sulfinyliminophenyl)- acetacetic acid(lower)a1kyl esters which are optionally substituted according to thedefinition for R and R with butadiene or alkyl substituted butadienes ofthe general formula XIV, as under formation of the l-pyrryl group thering contraction already occurs under reaction conditions which are notsufficient for splitting off according to the process to the alkalinesalts of monocarboxylic acids or occurs quicker under vigorous reactionconditions than the above-mentioned splitting off.

According to a sixth process, compounds of the general formula la areproduced by reacting a compound of the general formula VIII in which R Rhave the meanings given in formula I, in the presence of a silver salt,silver oxide, copper or platinum as catalyst with water, with a lowalkanol or another hydroxy compound, if desired hydrolyzing the lowalkyl ester so obtained or in any case hydrolyzing an ester with anotherhydroxy'compound and, if desired, converting a carboxylic acid soobtained into a salt with an inorganic or organic base. For example, asolution of the diazoketone of the general formula VIII is slowly addedto aqueous solution of silver nitrate and sodium thiosulphate or to asuspension of silver oxide in an aqueous solution of sodium thiosulphatewhereby the temperature of the aqueous solution or suspension is about6070 According to an advantageous modification of the process, freshlyprepared silver oxide is mixed portionwise into a solution of thediazoketone in a low alkanol at the boiling temperature of the latteruntil no further evolution of nitrogen can be ascertained, and ifdesired, the resulting low alkyl ester is hydrolyzed for example bymeans of alkanolic potassium hydroxide solution or sodium hydroxidesolution while heat ing. Starting materials of the general formula VIIIcan be produced by reaction of p-( l-pyrrl)-benzoyl-chloride which issubstituted according to the definition for R R and R with diazomethane,by methods already known per se. The necessary acid chlorides are inturn obtained by condensing pamino benzoic acid which is optionallysubstituted according to the definition of R with a compound of theabove given general formula III, analogously to the first given processfor the production of compounds of the general formula I, and then bytreating the optionally substituted p-( l-pyrrl)-benzoic acid soobtained with thionyl chloride in the presence of an acid binding agent,such as pyridine, or with oxalyl chloride.

According to a seventh process, compounds of the general formula I inwhich R is a low alkyl group, are obtained by treating a compound of thegeneral formula IX in which R, and R represent hydrogen or low alkylgroups of together at most for carbon atoms, and

R R R and R have the meanings given in formula I, with catalyticallyactivated or nascent hydrogen until substantially equimolar amounts havebeen absorbed, and if desired converting the carboxylic acid so obtainedinto a salt with an inorganic or organic base. For example, a compoundof the general formula IX is hydrogenated in the presence of a pre ciousmetal catalyst such as platinum on charcoal, in glacial acetic acid orethanol under normal or moderately raised pres sure, or such a compoundis reduced by means of sodium and a low alkanol or by means of sodiumamalgam and water.

Starting materials of the general formula IX are for example produced byreacting metal organic compounds of p-( l-pyrryl)-phenyl, e.g., of p-(l-pyrryl)-phenyllithium or p-( l-pyrryl)-phenyl magnesium bromide whichare optionally substituted according to the definition for R R and R,with pyruvic acid or other, lower 2-ox0alkane acids to optionallysubstituted 2-[p-( l-pyrryl)-phenyl]- 2-hydroxy-alkane acids and ifdesired by reacting these in lower alkyl estersand in any case finallyby splitting off water, e.g., by heating with mineral acids. The abovementioned 2-[p-( l-pyrryl)-phenyl]-2hydroxy-alkane acids and their loweralkyl esters correspond to the general formula IXa mentioned below. Thesubstituted 2- hydroxy alkane acids of this general formula can also beprepared by a further metal organic reaction consisting of the reactionof p-(l-pyrryl)-phenyl glyoxyl acids which are optionally substitutedaccording to the definition for R R and R, with lower alkyl magnesiumhalogenides. Substituted 2- hydroxy alkane acids of the general formulaIXa with hydrogen atoms as R, and R are also obtained for example byaddition of cyanic acid to be substituted acetophenones of the generalformula XI mentioned below, by hydrolyzing in the cold obtained cyanohydrines with cone. mineral acids to the corresponding substituted2-hydroxy alkane amides and further hydrolyzing of the latter by meansof alkali lyes while heating.

Another approach to the starting materials of the general formula IXwithv hydrogen atoms as R, and R consists in reducing p-nitro-atropicacid to p-amino atropic acid and condensing the latter with a compoundof the general formula II analogously to the first mentioned process forthe production of compounds of the general formula I. Starting materialsof the general formula IX with low alkyl groups as R and R, can beproduced, for example, by condensing p-nitro-phenylacetonitrile with lowdialkyl-ketones in the presence of sodium alcoholates, hydrolyzing thenitrile so obtained, reducing the nitro group and again condensing withcompounds of the general formula III.

According to a modification of the process mentioned above a compound ofthe general formula IXa wherein R R R R and R have the meanings given informula] and formula IX, respectively,

is reduced instead of a compound of the general formula IX and, ifdesired, the carboxylic acid obtained is converted to a salt with aninorganic or organic base. The reduction of the compounds of the generalformula IXa takes place for example by means of tin(II)-chloride in amixture of hydrochloric acid and acetic acid or by means of iodine andphosphorus in acetic acid. The reductions are performed preferably atelevated temperature, e.g., at the boiling temperature of the reactionmixture mentioned.

The starting materials of the general formula IXa have been mentionedabove as intermediate products for the production of compounds of thegeneral formula IX. The present modification of the eighth process forthe production of the compounds of the general formula I is thus asingle step variation of a double step reaction sequence according towhich first compounds of the general formula IXa are converted intocompounds of the general formula IX by splitting off water and thelatter are hydrogenated or reduced to form compounds of the generalformula I.

While according to the preceding processes, carboxylic acids as well astheir low alkyl esters can be produced, carboxylic acids having generalformula I and their salts with inorganic and organic bases are obtainedaccording to an eighth process in which a functional derivative of acarboxylic acid of this general formula is hydrolyzed, the acidoptionally liberated from the obtained salt and/or an acid so obtainedconverted into a salt. As starting material can be chosen for examplethe low alkyl esters which also have general formula I or suchfunctional derivatives of free carboxylic acids of the general formulaI, which can be easily obtained analogously to various previouslymentioned processes for the production of free carboxylic acids andalkyl esters thereof by using other starting materials and/ormodifications of the given processes. This is particularly true fornitriles, but also for amides as well as for esters with other hydroxycompounds such as low alkanols.

Preferably according to the process a starting compound of the generalformula X I N CH-A4 in which A represents the cyano group, an optionallysubstituted carbamoyl group or a carboxylic acid ester group or imidoester group, particularly the cyano or carbamoyl group, and R R R and Rhave the meanings given in formula I, is hydrolyzed in an alkaline oracid medium, and if desired, the carboxylic acid falling under generalformula I is liberated from the salt obtained or a carboxylic acid soobtained is converted into a salt with an inorganic or organic base.

Nitriles, and esters, i.e., apart from low alkyl esters for examplecycloalkyl esters and phenyl esters, as well as N,N-disubstituted amidesespecially low N,N-dialkyl amide, pyrrolidide, piperidide andmorpholide, may also be obtained, and can be used as starting materialsfor the hydrolysis, for example, by a method analogous to the firstmentioned process" for the production of compounds of general formula I,by using the corresponding functional derivative instead of the freecarboxylic acids or their low alkyl esters of the general formula l.Starting materials of the general formula X in which R represents a lowalkyl group, alkenyl group or alkinyl group, are obtained analogously tothe fourth production process. Especially important is the use of thisprocess for the production of nitriles which are derived from thecarboxylic acids having the general formula I. Thereby, as in theproduction of alkyl esters, in relation to the nitrile an equimolaramount of an alkaline condensing agent is to be used. Examples of suchagents are: sodium amide, lithium hydride, sodium hydride, butyllithium, phenyl lithium, triphenyl-methyl sodium, sodium methylate,potassium methylate, sodium isopropylate, sodium-tert.amylate, potassiumhydroxide or sodium hydroxide, and as reaction medium for example, inertorganic solvents such as diethylether, benzene and toluene, or,

together with the above mentioned alkali metal alcoholates or alkalimetal hydroxides as condensing agent, also low alkanols such as ethanolor methanol. Also analogous to a modification of the fifth mentionedprocess, nitriles of the general formula X can be produced instead ofthe free carboxylic acids and alkyl esters, by decarboxylating thecorresponding nitrilic acids instead of the free dicarboxylic acids ordicarboxylic acid monoalkyl esters of the general formula Vlla. Thecompounds mentioned are in turn obtained for example by partialhydrolysis of corresponding cyano acetic acid (lower)alkyl esters, bymeans of sodium hydroxide solution, at room temperature or slightlyraised temperature. The nitrile of the corresponding carboxylic acid ofthe general formula I is obtained analogously to the fifth mentionedprocess by reacting 2-[p-(l -PYRRYL)-phenyl]-acetylacetonitrile, whichcan be substituted according to the definition of R R and R with ananhydrous alkali alcoholate solution. Finally, nitriles of carboxylicacids having the general formula I, which nitriles also have the generalformula X and are suitable for hydrolysis, are obtained by reacting p-(1-pyrryl)-benzyl halides which are substituted according to thedefinition of R R R and R with alkali metal cyanides. Instead ofhydrolyzing nitriles of the general formulaX, directly to carboxylicacids of the general formula 1, they can first be converted into thecorresponding amides which also have the general formula X by treatingthem with alkaline hydrogen peroxide solution and then hydrolyzing ifnecessary in the same operation, to the carboxylic acids of the generalformula I. The imido esters or hydrochlorides thereof which can also beused as starting materials of the general formula X are formed by thesuccessive reaction of hydrogen chloride and a low alkanol on thecorresponding nitrile in an anhydrous medium, especially in absoluteether.

According to a ninth process carboxylic acids having the narrowergeneral formula Ia are obtained by heating a compound of the generalformula XI N co-om in which R R and'R,'have the meanings given informula I, with ammonium polysulfide or ammonia or with a primary orsecondary amine and sulphur according to the methods of Willgerodt andWillgerodt-Kindler, hydrolyzing the amide, or optionally monoordisubstituted thioamide, so obtained, if desired, liberating thecarboxylic acid having the general formula I from the salt so obtainedand converting it into a salt with an inorganic or organic base, ifdesired. The reaction of a compound of the general formula XI withammonium polysulphide is carried out for example, in a medium in whichone, or preferably both, reaction components are at least partiallysoluble, such as dioxan, in a closed vessel at temperatures of about220. According to Kindlers modification, a compound of the generalformula XI can be reacted for example with aqueous or anhydrous ammoniaor with a low monoalkylarnine or low dialkylamine or piperidine, andwith sulphur, also in a closed vessel and optionally in the presence ofpyridine at temperatures of about 140 180. According to the mostcommonly used method of carrying out the Kindler modification,morpholine is used as the amine, and the boiling point of l38 of themorpholine renders the use of pressure vessels unnecessary. For example,the compound of the general formula XI and sulphur are refluxed inexcess morpholine for some time, e.g., about 5 40 hours and theresulting morpholide of a thio acid corresponding to the general formulaXII wherein R R and R have the meanings given in formula I, ishydrolyzed, e.g., by boiling with alkanolic or alkanolic-aqueouspotassium hydroxide solution or sodium hydroxide solution.

The compounds of the general formula XI which are required as startingmaterials, can be obtained for example by condensing4'-aminoacetophenone which is optionally substituted according to thedefinition for R with a compound of the general formula III given aboveanalogously to the first mentioned process for the production ofcompounds of the general formula 1.

A 10th process for the production of compounds of the general formula Iconsists of reacting a compound of the general formula XIII wherein Rand R have the meanings given in formula I, and treating the reactionproduct of the general formula XV wherein R represents a low alkylgroup, and

R R R and K, have the meanings given in formula I, with an alkali metalhydroxide, if desired liberating the carboxylic acid having the generalformula I from the alkali salt so obtained and if desired converting itinto a salt with an inorganic or organic base. For example, a compoundof the general formula XIII is heated with at least the equimolar amountof a compound of the general formula XIV, such as butadiene, isopren or2,3-dimethyl-butadiene, for a long period of time in an organic solventsuch as acetonitrile or cyclohexane, until the addition is complete. Thecrude reaction product of the general formula XV is refluxed for examplewith potassium hydroxide in a low alkanol such as ethanol whereby ringcontraction and, at the same time, hydrolysis of the ester group occurs.

The starting materials of the general formula XIII can in turn beobtained by reacting low alkyl esters having the general formula II,with thionyl chloride.

According to an eleventh process a carboxylic acid having the generalfonnula I is converted into a low alkyl ester. For example, a carboxylicacid having the general formula I is reacted with a low diazoalkane,especially diazomethane, or in the presence of a dehydrating agent, suchas hydrogen chloride, sulphuric acid, p-toluene sulphonic acid ordicyclohexyl-carbodiimido, with a low alkanol. According to a variationof the esterification the carboxylic acid having the general formula Iis first-converted into a reactive functional derivative and the latteris reacted, optionally in the presence of an acid binding agent, with alow alkanol. For example, by heating the carboxylic acid with thionylchloride in the presence of an acid binding agent such as pyridine, orwith oxalyl chloride, the corresponding carboxylic acid chloride isobtained which yields the corresponding low alkyl ester on reacting witha low alkanol. According to another variation of the esterification, thecarboxylic acid is converted into a metal salt, particularly an alkalimetal salt, silver salt or lead salt, and this is then reacted with areactive ester of a low alkanol, for example with a low alkyl halide,low p-toluene sulphonic acid alkylester or dimethylsulphate. Thereaction can optionally be carried out in an organic solvent such asbenzene, toluene, ether, tetrahydrofuran or dioxan, and completed byheating.

Finally, the low alkyl esters having the general formula] are producedby a 12th process in which a nitrile of the general formula XVI in whichR R R and R have the meanings given under formula l, is subjected toalcoholysis. The alcoholysis is carried out by simultaneous orsuccessive treatment with a mineral acid, a low alkanol and, optionally,of water. For example, a

nitrile of the general formula XVI is treated with hydrogen chloride inthe cold, the resulting imide chloridehydrochloride is reacted with alow, anhydrous alkanol to fonn the correspondingimido-alkylester-hydrochloride, and the latter is decomposed with waterto the corresponding low alkylester having the general formula I. Thenitriles of the general formula XVI which are required as startingmaterials are embraced by the above given general formula X and theirproduction is more closely explained following that formula.

According to the invention compounds of the general formula I, wherein Rrepresents a low alkyl or alkinyl group are obtained as racemates of theoptically active and forms, if in suitable processes therefor, opticallyactive starting materials are not used. The racemates may be resolvedinto the optically active enantiomers by known means. For example theracemate free carboxylic acids having the general formula I are reactedwith optically reactive organic bases, such as and (-)-a-phenylethylamine and ()-amethyl-benzylamine], cinchonidine or cinchonine orbrucine in organic solvents or in water to pairs of diastereomers, fromwhich the more difficulty soluble one is separated, optionally afterconcentration and/or cooling. Such organic solutions are chosen whereinthe two enantiomeric salts have the greatest difference in solubilitypossible, so that an optimal separation can be obtained, and optionallythe amount of the optically active base used can also be reduced to halfof the equimolar amount. For example the salt formation can be performedin a low alkanol, such as ethanol or isopropanol in acetone or dioxaneor in a mixture thereof or of further solvents. The optically activeforms generally show great difierences in their pharmacologicalproperties, for example the (+)-2-[p-(l-pyrryl)- phenyl]-butyric acidshows stronger analgesic and antiphlogistic activities than the()-2-[p-(1-pyrryl)-phenyl]-butyric acid.

As stated above the invention also concerns the conversion of thesubstituted phenyl acetic acids of the invention into salts withinorganic or organic bases, which is effected according to the usualmethods well known in the art.

Salts suitable for therapeutic use are those with pharmacologicallyacceptable inorganic or organic bases, i.e., with bases which, in theusual dosages, have no physiological action of their own or, however,have a desired action, e.g., in forms for parenteral administration,particularly a local anaesthetic action. Suitable salts are, e.g.,sodium salts, potassium salts, lithium salts, magnesium salts, calciumsalts and ammonium salts, as well as salts with ethylamine,triethylamine, Z-aminoethanol, 2,2'-imino-diethanol,2-dirnethylamino-ethanol, 2-

diethylamino-ethanol, ethylenediamine, benzylamine, procaine,pyrrolidine, piperidine, morpholine, l-ethylpiperidine or2-piperidino-ethanol or with basic ion exchangers.

The substituted phenyl acetic acids and the esters thereof correspondingto the above formula I, as well as the addition salts of the carboxylicacids having the formula I with inorganic or organic bases, have nowbeen found to exhibit valuable pharmacological properties, in particularanti-inflammatory (antiphlogistic), analgesic and antipyretic activitycombined with a favorable therapeutic index. At the same time they areespecially distinguished by their good compatibility with the gastricsystem, particularly in not causing undue gastric irritation as well asby the advantageous fact that they do not influence the central nervoussystem. These favorable properties render the inventive compounds wellsuited for .the treatment, relief and removal, of pain of variousorigin, as well as for the treatment and alleviation of acute andchronic inflammatory disorders such as rheumatoid arthritis, rheumaticfever and the like.

Particularly advantageous compounds according to the invention aresubstituted phenyl acetic acids and esters thereof which correspond tothe above formula I wherein R represents hydrogen, straight-chain loweralkyl, straightchain lower alkenyl or straight-chain lower alkinyl,

R represents hydrogen, methyl, methoxy, chlorine or bromine,

R and R represent hydrogen, and

R represents hydrogen or lower alkyl, as well as the addition salts ofthe carboxylic acids according to the aforegiven definition withinorganic or organic bases. Within this scope compounds wherein Rrepresents hydrogen are especially distinguished for their use asanalgesics.

Representative of these compounds are particularly [p-(l-pyrryl)-phenyl]-acetic acid,

2-[p-( 1-pyrryl)-phenyl]-propionic acid,

2-[p-( l-pyrryl)-phenyl]-butyric acid,

[3-chloro-4-( l-pyrryl)-phenyl]-acetic acid,

2-[3-chloro-4-( l-pyrryl)-phenyl]-propionic acid,

[p-( l-pyrryl)-phenyl]-acetic acid ethyl ester, and

2-[p-( l-pyrryl)-phenyl]-propionic acid methyl ester, as well as theaddition salts of the carboxylic acids among them with inorganic ororganic bases.

The anti-inflammatory (antiphlogistic) activity of the inventivecompounds can be studied in pharmacological tests, e.g., in the Bolusalba edema test according to G. WILHELMI, J ap. J. Pharmacol. 15, 1871965), in the rat.

It is found that, e.g., 2-[p-(1-pyrryl)-phenyl]-propionic acid whenadministered in this test to rats shows already at dosages of 50 mg/kgp.o. distinct antiphlogistic action. A similar effect is shown by, e.g.,2-[3-chloro-4-(1-pyrryl)-phenyl]- propionic acid on administration atthe same dosage levels, i.e., at 10- 50 mg/kg p.o. rat.

Moreover, a strong anti-preinflammatory activity (which according to theW.T. BEAVER, Am. J. Med. Sci. 250, 581 (1965) is considered anadjunctive property of mild analgesics) can be demonstrated by theability of the inventive compounds to delay the appearance of erythemain the skin of guinea pigs exposed to ultraviolet light, whenadministered before the application of the UV. radiation.

For example, 2-[p-( l-pyrryl)-phenyl]-propionic acid or, for example,2-[p-( l-pyrryl)-phenyl]-butyric acid, show in this U.V. erythema test(technique of G. WILHELMI, Schweizerische Medizinische Wochenschrift 79,577 (1949)) on administration of only l-2 mg/kg p.o. to guinea pigs 2hours before the application of the ultraviolet light excellentantipreinflammatory activity.

In the writhing test according to E. SIEGMUND, R. CAD- MUS and C. LU,Proc. Soc. Exp. Biol. Med. 95, 729 (1957), distinct analgesic activityis demonstrated by, e.g., [p-( l-pyrryl)-phenyl]-acetic acid or, e.g.,2-[p-(l-pyrryl)-phenyl]-butyric acid or, e.g., [p-( l-pyrryl)-phenyl]-acetic acid ethyl ester, when administered in dosages of about10-70 mg/kg p.o. to mice.

The excellent compatibility of the inventive compounds with the gastricsystem can be demonstrated in the test according to G. WILHELMI,Arzneimittelforschung l0, l0 1960) which comprises administering to asignificant number of rats the compounds to be tested in two dosagesp.o. (the second dosage "about hours after the first), sacrificing theanimals 21 hours after the'first application of the compounds andmacroscopically inspecting a development of stomach-ulcers. For example,2-[p-( l-pyrryl)-phenyl]-butyric acid administered in two dosages of 100mg/kg p.o. each, showed in this test no significant gastric irritation.I A M As mentioned above the compounds according to the invention havean excellent therapeutic index, their toxicity being low. The LD is,e.g., for [p-( l-pyrryl)-phenyl]-acetic acid as low as 5,000 mg/kg p.o.mice.

For their intended uses the compounds of the invention are administeredorally, rectally or, particularly in the form of aqueous solutions ofthe salts of the carboxylic acids corresponding to formula 1, or in theform of aqueous dispersion, also parenterally, particularlyintramuscularly, in amounts depending on the species, age and weight ofthe subject under treatment as well as on the particular condition to betreated and, of course, the mode of administration; generally the dailydoses of the compounds of formula I as well as the pharmaceu- LIItically acceptable addition salts of the acids having this formula withinorganic or organic bases vary between and 3,000 mg.

For administration purposes, preferably, the above mentioned therapeuticcompositions are used. These compositions are presented for oral, rectalor parenteral administration in dosage units such as tablets, dragees(sugar coated tablets), capsules, suppositories or ampoules, preferablycontaining as active substance 10 500 mg of a compound of the formula Ior of a pharrnaceutically acceptable addition salt of an acid havingthis formula with an inorganic or organic base.

As active substance of compounds of the general formula I, wherein R, isother than hydrogen, as well as the corresponding salts, the racemate aswell as an optically active enantiomer can be used.

In unit dosage forms for oral administration the content of activesubstance is preferably between 10 and 90 percent. For the production ofsuch unit dosage forms, the active substance is combined, for example,with solid, pulverulent carriers, such as lactose, saccharose, sorbitol,mannitol; starches such as potato starch, maize starch or amylopectin,laminaria powder and citrus pulp powder; cellulose derivatives orgelatine, optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols to form tablets or drageecores. The latter may be coated, e.g., with concentrated sugar solutionswhich can also contain, e.g., gum arabic, talcum and/or titaniumdioxide, or with a lacquer dissolved in easily volatile organic solventsor mixtures of solvents. Dyestuffs can be added to these coatings, e.g.,to distinguish between different dosages of active substance. Otherdosage units suitable for oral administration are hard gelatine capsulesas well as soft closed capsules made ofg'elatine and a softener such asglycerine. The former preferably contain the active substance as agranulate in admixture with lubricants such as talcum or magnesiumstearate and, optionally, stabilizers such as sodium metabisulphite (NaS,0 or ascorbic acid. In soft capsules, the active substance ispreferably dissolved or suspended in suitable liquids such as, liquidpolyethylene glycols, to which stabilizers can also be added.

Examples of dosage units for rectaladministration are suppositorieswhich consist of a combination of an active substance with a suppositoryfoundation mass based on natural or synthetic triglycerides (e.g., cocoabutter), polyethylene glycols or suitable higher fatty alcohols, andgelatine rectal capsules which contain a combination of the activesubstance with polyethylene glycols.

Ampoule solutions for parenteral especially for intramuscular orintravenous administration contain, e.g., a compound of general formulaI in a concentration of, preferably, 0.5 to 5 percent as aqueousdispersion prepared with the aid of the usual solubility promotersand/or emulsifying agents as well as, optionally, stabilizers, or theycontain an aqueous solution of a pharrnaceutically acceptable, watersoluble salt of a free acid embraced by the general formula 1.

Further parenteral forms for percutaneous application are, e.g.,lotions, tinctures or ointments prepared with the usual additives.

The following prescriptions further illustrate the production ofdifferent unit dosages and forms of application.

a. 1,000 g of active substance, e.g., 2-[p-( l-pyrryl)-phenyl]- butyricacid are mixed with 550 g of lactose and 292 g of potato starch, themixture is moistened with an alcoholic solution of 8 g of gelatine andgranulated through a sieve. After drying, g of potato starch, 60 g oftalcum and 10 g of magnesium stearate and 20 g of highly dispersedsilicon dioxide are mixed in and the mixture is pressed into 10,000tablets each weighing 200 mg and containing 100 mg of active substance.If desired the tablets can be grooved for better adaptation of thedosage.

b. 200 g of active substance, e.g., [p-( 1-pyrryl)-phenyl]- acetic acid,are well mixed with 16 g of maize starch and 6 g of highly dispersedsilicon dioxide. The mixture is moistened with a solution of 2 g ofstearic acid, 6 g of ethyl cellulose and 6 g of stearin in about ml ofisopropyl alcohol and granulated through a sieve III (Ph- Helv. V). Thegranulate is dried for about 14 hours and then pressed again throughsieve Ill-Illa. It is then mixed with 16 g of maize starch, 16 g oftalcum and 2 g of magnesium stearate and pressed into 1,000 drageecores. These are then coated with a concentrated syrup of 2 g ofshellac, 7.5 g of gum arabic, 0.15 g of dyestuff, 2 g of highlydispersed silicon dioxide, 25 g of talcum and 53.35 g of sugar, anddried. The dragees obtained each weigh 360 mg and contain 200 mg ofactive substance.

c. 50.0 g of 2-[p-(1-pyrryl)-phenyl]-propionic acid are dissolved in amixture of 232 ml 1N sodium hydroxide solution and 500 ml of pyrogenfree boiled water and the solution is made up to 2,000 ml with the samewater. The solution is filtered, filled in 1,000 ampoules of 2 ml eachand sterilized. One ampoule of 2 ml contains 50 mg of 2-[p-(1-pyrryl)-phenyl]-propionic acid as active substance in the form ofits sodium salt.

. 50 g of 2-[p-( l-pyrryl)-phenyl]-butyric acid and 1,950 g finelyground basic substance for suppositories (e.g.,

cocoa butter) are thoroughly mixed and then melted. 1,000 suppositoriesof 2.0 g each are cast from the melt kept homogenous by stirring. Eachcontains 50 mg of active substance.

. 60.0 g of polyoxyethylene sorbitan monostearate, 30.0 g of sorbitanmonostearate, 150.0 g of paraffin oil and 120.0 g stearyl alcohol aremelted together; 50.0 g of [p- (l-pyrryl)-phenyl]-acetic acid (finelypulverized are added and 590 ml water preheated to 40 emulsifiedtherein. The emulsion is stirred until cooled to room temperature andthen filled into vials.

The following examples further illustrate the production of the newcompounds of general formula I but they in no way limit the scope of theinvention. The temperatures are given in degrees Centigrade, percentagesare given by weight. Torr means mm Hg.

EXAMPLE 1 179 g (1 mol) of 2-(p-aminophenyl)-butyric acid (Fourneau,Sandulesco, B1. [4], 452) and 132 g (1 mol) of 2,5-'dimethoxy-tetrahydrofuran in 200 ml of glacial acetic acid are refluxedfor minutes. The reaction mixture is then distilled from an oil bath,first under 12 Torr and then under high vacuum. The fraction whichpasses over between 180 200 under 0.5 1 Torr consistsof crude2-[p(1-pyrryl)-phenyl]- butyric acid. It crystallizes during thedistillation, M.P. 105l 10. On recrystallizing from benzene/cyclohexane1:1, 660 ml) and decoloring with active charcoal, washing the crystalswith the same mixture of solvents (l 10 ml) and drying for 15 hours at50 under 0.5 Torr, pure 2-[p-( l-pyrryl)-phenyl]-butyric acid isobtained which melts at l 12l 13. It has an immediate positive reactionto Ehrlich reactant (pdimethylamino benzaldehyde).

On reacting p-arnino-hydrotropic acid (rac., F. Nerdel, l-l.Pawlowski,Chem. Ber. 87, 217-220 (1954)) with the equimolar amount of2,5-dimethoxy-tetrahydrofuran, p-( lpyrryl)-hydratropic acid is obtainedin an analogous manner; M.P. l66l68.

1f 2-(p-aminophenyl)-butyric acid is reacted with an equimolar amount of2,5-dimethoXy-3-methyl-tetrahydrofuran in an analogous manner to thefirst paragraph, 2-[p-(3- methyl-l-pyrryl)-phenyl]-butyric acidwith M.P.138139 is obtained. The 2,5-dimethoxy-3-methyl-tetrahydrofuran, B.P.157-l 58/760 Torr, N 1.4169, is produced starting from 3- methyl-furanby conversion into the 2,5-dimethoxy-3-methyl- 2,5'dihydrofuran. B.P.l7l-l 72/760 Torr, N 1.4358, analogously to the corresponding 2-methylcompound [Clauson-Kaas, Limborg, Dietrich, Acta Chem. Scand. 6, 545(1952)] and reduction analogously to the production of the:2,5-dimethoxy-Zmethyl-tetrahydrofuran Clauson-Kaas Elming, Acta Chem.Scand. 6, 867 (1952)].

By reaction of 2-(p-aminophenyl)-valeric acid with the equimolar amountof 2,5-dimethoxy-tetrahydrofuran the 2-[p- (1-pyrryl)-phenyl]-va1ericacid, M.P. 108109 is also analogously obtained.

EXAMPLE2 30.2 g (0.20 mol) of (p-aminophenyD-acetic acid [Radziszewski,Ber. 2, 209; Bedson, J. Chem. Soc. 37, 92] and 26.4 g (0.20 mol) of2,5-dimethoxy-tetrahydrofuran in 40 ml of acetic acid are refluxed for30 minutes. After cooling, the reaction solution is poured into 160 mlof water. The precipitated crystals are filtered off, washed with waterand dried for 15 hours at 70. The brown powder obtained is extractedwith benzene in a Soxhlet apparatus. On concentrating the extract, the[p-(1-pyrryl)-phenyl]-acetic acid which melts at 180-182 and has apositive Ehrlich reaction is obtained.

EXAMPLE 3 3.58 g (0.020 mol) of 2-(p-aminophenyl)-butyric acid and 2.28g (0.020 mol) of acetonyl-acetone in 7 ml acetic acid are refluxed for30 minutes. The clear, red reaction mixture is evaporated to dryness onthe water-bath under 10 Torr. The solid residue (5.3 g) is dissolved in150 ml of ether, the ether solution is washed with 15 ml 3-Nhydrochloric acid and several times with water, dried over magnesiumsulphate and concentrated. The reddish brown, crystalline residue whichmelts at 143 is sublirnated at 150 under 0.1 Torr. The sublimate isrecrystallized from benzene-cyclohexane and then from methanol-water andthen once more Sublimated, whereby2-[p-(2,5-dimethyl-1-pyrryl)phenyl]-butyric acid is EXAMPLE 4 21.4 g of(p-aminophenyl)-acetic acidethylester, 15.9 g of2,5-dimethoxy-tetrahydrofuran and 30 ml of glacial acetic acid arerefluxed for 1% hours. The solvent is distilled off under water jetvacuum. The residue is distilled in high vacuum, whereupon the[p-(1-pyrryl)-phenyl]-acetic acidethylester passes over at l22-130/0.02Torr. After recrystallization from methanol it melts at 495 1.

EXAMPLE 5 3.58 g (0.02 mol) of 2-(p-aminophenyD-butyric acid and 2.10 g(0.01 mol) of mucic acid are dissolved by boiling in 50 ml of water. Theclear solution is evaporated to dryness and the residue is Sublimatedunder high vacuum (0.4 Torr) at l70230. The pale yellow sublimate iscrystallized from benzene whereupon Z-[p-(l-pyrryD-phenyll-butyric acidis obtained, M.P. 109112. After recrystallization from ether, themelting point is l l2-l 13.

EXAMPLE 6 To ml of liquid ammonia is added while stirring enough of 1.45g (0.063 mol) of sodium to produce a distinctly blue solution, a fewcrystals of iron(lll)nitrate are added thereto and then the remainingsodium and stirring is continued till the blue color has disappeared anda grey sodium-amide suspension is formed (see Organic Reactions 8,122[1954]). 6.03 g (0.025 mol) of [p-(l-pyrryl)-phenyl]-acetic acid (cf.Example 2) is added to this suspension. The mixture is refluxed for 30minutes while stirring. A solution of 2.73 g (0.025 mol) of ethylbromidein 5 ml ether is added dropwise within 2 minutes, and the reactionmixture is further refluxed and stirred for 30 minutes. 3.8 g (0.07 mol)of ammonium chloride are added and the ammonia is evaporated with thegradual addition of 150 ml of ether. The practically ammoniafreeethereal solution is extracted with 25 ml of 3-N hydrochloric acid. Theaqueous phase is in turn extracted twice with ether. The ether phasesare combined, dried over magnesium sulphate and evaporated to dryness.The residual crude product melts partially at 109l 12. It is thenrecrystallized from about 20 ml benzene-cyclohexane (1:1) and then fromabout 35 ml methanol-water (3:2), whereupon 2-[p-( lpyrryl)-phenyl]-butyric acid is obtained, M.P. l l2l 13.

Analogously, by using 0.025 mol of n-propyl-bromide, isopropyl-bromide,allyl-bromide or 2-propinyl-bromide are obtained 2-[p-(1-pyrryl)-phenyl]-valeric acid, M.P. 108-l09,

2-[p-( l-pyrryl )-phenyl]-4-pentinic acid, M.P. 122123 respectively.

EXAMPLE 7 Analogously to Example 6, 10.1 g (0.05 mol) of [p-(l-pyrryl)-phenyl]-acetic acid are reacted with 6.85 g (0.05 mol) ofl-bromine-butane, using a sodium-amide suspension prepared from 2.9(0.125 mol) of sodium and 250 ml of liquid ammonia. The crude product isdistilled in high vacuum and the fraction which passes over under 0.2Torr at 17ll80 is crystallized from a mixture of 40 ml of petroleumether (B.P. up to 50) and 20 ml cyclohexane, and then from a mixture ofml each of petroleum ether and cyclohexane and finally from mlmethylcyclohexane, whereupon pure 2-[p-(1-pyrryl)-phenyl]-hexanoic acidis obtained as yellowish-white crystals, M.P. 9698.

EXAMPLE 8 Analogously to Example 6, 15.1 g (0.075 mol) of [p-(l-pyrryl)-phenyl]-acetic acid are reacted with 13.7 g (0.097 mol) ofmethyl-iodide using a sodium-amide suspension prepared from 4.32 g(0.188 mol) sodium and 300 ml of liquid ammonia. After in all sixcrystallizations from benzene, methanol-water and methanol the crudeproduct afiords the 2-[p-( l-pyrryl)-phenyl]-propionic acid as whitecrystals, M.P. 168-l69.

EXAMPLE 9 7.4 g p l-pyrryl)-benzoic acid with 3.3 ml of thionylchlorideand 4.8 g of pyridine in 100 ml methylenechloride are heated to boilingunder reflux for 3 hours in a nitrogen atmosphere. The reaction mixtureis then evaporated in vacuum and the residue is mixed with 100 mltetrahydrofuran, whereby a part thereof remains undissolved. Theresulting suspension of crude acid chloride is added dropwise within anhour, while cooling with ice, to a mixture of 200 ml 0.6-N etherealdiazomethane solution and 50 ml of dioxane and the whole is then stirredfor 18 hours at room temperature. A solution is thus formed which isfreed from a slight turbidity by filtration through Hyflo (diatomaceousearth), and the filtrate is evaporated under reduced pressure at 30.

The residual, raw 4'-(1-pyrryl)-2-diazo-acetophenone is dissolved in 180ml abs. methanol, the solution is heated to boiling under reflux, and ismixed portionwise with silveroxide (produced from 2 g of silver nitrateand washed with methanol) until no further gas evolution can bedetermined, which takes about 4 hours. The silver precipitate isfiltered off, the filtrate is evaporated under vacuum and the partiallycrystalline residue of crude [p-( l-pyrryl)-phenyl]-aceticacidmethylester is refluxed for 3 hours with a solution of 4 g potassiumhydroxide in 5 ml of water and 50 ml of methanol. After distilling thesolvent off under vacuum, the residue is dissolved in 30 ml ofmethanol-water (1:1) and neutralized with glacial acetic acid. The crude[p-(l-pyrryl)-phenyl)]-acetic acid so obtained has a M.P. of 170180. Byrecrystallizing several times from carbon tetrachloride-ethyl acetatethe melting point is raised to l80l 82.

The p-( l-pyrryl)-benzoic acid used as starting material is obtained asfollows:

a. The p-( I-pyrryD-benzoic acid-ethylester is produced analogously tothe 4-(1-pyrryl)-acetophenone [cf. Example 1241)], from2,5-dimethoxy-tetrahydrofuran and 4- amino-benzoic acid-ethyl ester,M.P. 7576 (from methanol), B.P. 140l45/ 0.01 Torr.

b. A solution of 32 g of p-( 1-pyrryl)-bnzoic acid-ethylester and 12 gof sodium hydroxide in 600 ml ethanol is heated to boiling under refluxfor 2 hours, whereupon a crystalline precipitate gradually forms. Thereaction mixture is then concentrated to about 200 m1 under reducedpressure and the precipitated sodium salt is brought to a solution bythe addition of 200 ml of water. This solution is then slowly brought topH 5 by means of glacial acetic acid while stirring, whereupon thedesired p-( lpyrryl)- benzoic acid precipitates as a fine, thick slurry.The precipitate is filtered ofl" under suction, washed portionwise withml of water and dried for 7 hours at 70 in a thermal vacuum dessicator.The p-( I-pyrryD-benzoic acid so obtained melts at 265270 withdecomposition.

EXAMPLE l0 A solution of 40g of [p-(1-pyrryl)-phenyl]-aceticacidethylester (cf. Example 4) and 7.2 g of sodium hydroxide in amixture of 200 ml each of water and ethanol, is refluxed for 5 hours.After evaporation in vacuum, the residue is dissolved in about 400 ml ofwater and extracted with 100 ml of ether. The aqueous phase is separatedoff, filtered and brought to pH 3-4 with about 6-N hydrochloric acid.The precipitated crystals are filtered off under suction, washed withwater and dried for 14 hours at 70, [p(1-pyrryl)-phenyl]-acetic acid,M.P. -182which sinters at 178 is so obtained. By recrystallization fromcarbon tetrachloride-methanol small colorless plates a a nnua 18 ?rEXAMPLE 11 9.10 g (0.05 mol) of [p-( l-pyrryl)-phenyl]-acetonitrile arerefluxed for 30 hours in a solution of 14 g (0.25 mol) of potassiumhydroxide in 70 ml of methanol and 10 ml of water. After cooling, thereaction solution is mixed with water and made acid with cone.hydrochloric acid. The carboxylic acid which separates off is taken upin ether and the ethereal solution is dried and concentrated. Theresidue is recrystallized from carbon tetrachloride-ethylacetate severaltimes, whereupon the [p-( l-pyrryl)-phenyl]-acetic acid is obtained,M.P. 180-1'82.

The new starting compound [p-(1-pyrryl)-phenyl]- acetonitrile isproduced as follows:

a. 17.8 g (0.135 mol) of (p-aminophenyl)-acetonitrile and 17.8 g (0.135mol) of 2,5-dimethoxy-tetrahydrofuran are refluxed for 2 hours in 47 mlof acetic acid. The dark reaction mixture is then evaporated on thewater-bath 100) under 10 Torr. The partially crystallized residue of24.5 g is continuously extracted with ether for 3 hours in a Soxhletapparatus. The ethereal suspension so obtained is concentrated to 50 mland cooled to 20. The substance which crystallizes out is filtered off,washed twice with ether and dried, whereupon [p-( l-pyrryl)-phenyl]-acetonitrile is obtained as light brown crystals, M.P. 100l02. Byrecrystallization from 260 ml isopropanol, while decoloring with activecharcoal, white, pure substance is obtained, M.P. 104-l05, which has apositive Ehrlich reaction.

EXAMPLE 12 3.7 g (0.02 mol) of 4'-(l-pyrryl)-acetophenone, 1.0 g ofsulphur powder and 4 ml of morpholine are refluxed for 15 hours. Thedark reaction mixture is thereupon mixed with 20 ml ethanol and 30 ml2-N sodium hydroxide solution and refluxed for a further 8 hours. Thevolatile portions are then evaporated in vacuum and the residue isdissolved in 30 ml of water and treated with active charcoal. Thesolution is then brought to pH l-2 with concentrated hydrochloric acid.The resulting precipitate is filtered ofi, washed with water till itshows only pH 3-4 and then dried in a thermal vacuum dessicator at about100 Torr and 50. 4.0 g of [p-( 1-pyrryl)-phenyl]-acetic acid are thusobtained as crystals with M.P. l60-l 7 0. Fiu'ther purification iscarried out by reprecipitation (sodium hydroxide; hydrochloric acid) andrecrystallization (once from ethanol and then once from carbontetrachloridemethanol); [p-(l-pyrryl)-phenyl]-acetic acid is soobtained,

M.P. 180182. Analogously when using 0.02 mol of the substituted4-pyrryl-acetophenone, mentioned under a), the following are obtained:

[3-bromo-4-( 1-pyrryl)-phenyl]-acetic acid,

[3-methyl-4( l-pyrryl)-phenyl-acetic acid, B.P. 180/0.02

Torr.; n 1,5785,

[3-methoxy-4-(1-pyrryl)-phenyl]-acetic acid, M.P. l2412 6(fromIsopropanol) [2-chloro-4-( l-pyrryl)-phenyl]-acetic acid.

The starting materials are produced as follows:

a. 13.5 g of 4'-amino-acetophenone and 13.2 g of cis, trans2,5-dimethoxy-tetrahydrofuran are refluxed for 2% hours in 25 ml ofglacial acetic acid. WHen left standing overnight, crystals separate offfrom the dark reaction mixture. These are filtered ofl and washed withether. 4'-( lpyrryl)-acetophenone is obtained, M.P. 1l8-l 22. Aftercrystallization from isopropanol the melting point is l20-122.

In an analogous manner, from 21.4 g 3'-bromo-4'-a.rninoacetophenonethere is obtained 3'-bromo-4'-( l-pyrryl)- acetophenone, starting from14.9 g 3'-methyl-4-amino-acetophenone there is obtained 3 '-methy1-4'-(1-pyrryl)-acetophenone, starting from 16.5 g3'-methoxy-4'-ami.no-acetophenone [see (b) and (c)]there is obtained3'-methoxy-4'-( l-pyrryl)- acetophenene, B.P. 220/0.05 Torr. M.P. 58-64and starting from 16.9 g 2'-chloro-4'-amino-acetophenone (prepared from3-chloro-acetanilide and acetylchloride analogous to2,2'-dichloro-4'-arnino-acetophenone [Kunckell et a1., Ber. 40,3394-3397 (1907) ]There is obtained 2- chloro-4-(l-pyrryl)-acetophenone.

b. In a 250 ml stirring flask with a stirrer, a dropping funnel and areflux condenser 2.7 g of magnesium filings with 2.5 ml of abs. ethanolare reacted with addition of a trace of iodine in 0.25 ml ofcarbontetrachloride. After the beginning of the reaction it is dilutedwith 37.5 ml of ether and a solution of 17.6 g of malonic acid ethylester, 10 ml of abs. ethanol and 12.5 ml of abs. ether is so added thatthe reaction mixture is kept boiling without external heating. It isrefluxed for 3 hours until all of the magnesium is dissolved. To thecooled clear solution there is added while stirring vigorously, anethereal solution of 21.5 g of crude 4-nitro-3-methoxy-benzoylchloridewhich has been previously refluxed for two hours with 19.7 g of4-nitro-3-methoxy-benzoic acid in 50 ml of thionylchloride and withdistilling off of the thionylchloride in vacuo. The reaction productseparates as a viscous mass. The reaction mixture is refluxed foranother half hour, cooled on ice and decomposed with about 100 ml of 2-Nsulphuric acid until the whole is dissolved. The other phase isseparated, combined with an ethereal extract of the aqueous phase,washed with water, dried over sodium sulphate and evaporated. The oilyresidue is taken up in a solution of 30 ml of glacial acetic acid, 3.75ml of cone. sulphuric acid and 20 ml of water and refluxed for 5 hoursuntil the evolution of carbon dioxide is completed. Then the solution ispoured on ice, made alkaline with 20 percent sodium hydroxide solutionand extracted several times with ether. The combined ether extracts arewashed with water, dried over sodium sulphate, and the ether isdistilled off. There is obtained crude 4-nitro-3-methoxyacetophenonewhich melts after recrystallization from ether at 6668.

. 7.35 g of 4-nitro-3 methoxy-acetophenone are dissolved in 90 ml ofglacial acetic acid. The solution is heated to about 70 on a water bathand a warm solution of 30 g of tin (ll) chloride in 36 ml conc.hydrochloric acid is added all at once. The reduction occurs immediatelywith boiling of the solution. The reaction mixture is allowed to cool toroom temperature, then poured on ice and made alkaline with 40 percentsodium hydroxide solution. The

reaction product is extracted with ether. The ether extract is washedwith water, dried over sodium sulphate and evaporated to dryness. Bycrystallization of the residue from ether-petroleum ether there isobtained 4- amino-3-methoxy-acetophenone as yellow prisms, M.P. 66-87.

EXAMPLE 13 21.2 g of 2-(p-sulphinylimino-phenyl)-butyric acid-ethylesterand 12 g of 2,3-dimethyl-1,3-butadiene are refluxed in 50 mlacetonitrile for 17 hours and then the reaction mixture is evaporated invacuum. The dark residue is refluxed for 2 hours with a solution of 30 gof potassium hydroxide in 250 ml of ethanol and after mixing with 200 mlof water is concentrated in vacuo to about 200 ml. The solution istreated with charcoal, brought to pH l-2 with 2 N hydrochloric acid andcooled. The resulting crystalline precipitate is filtered off undersuction, washed neutral with water and dried in a thermal vacuumdessicator. Crude 2-[p-(3,4-dimethyl-1-pyrryl)- phenyl]-butyric acid isso obtained, M.P. ll5l30. On recrystallization from isopropanol-waterand then from carbon tetrachloride, the melting point rises to 13 l-l32.

If the 2,3-dimethyl-l,3-butadiene is replaced by 11.5 g of isoprene(2-methyll ,3-butadiene), the 2-[p-( 3-methyll -pyrryl)-phenyl]-butyricacid is obtained in an analogous manner, M.P. l38-139.

In an analogous manner from 1,3-butadiene the2-[p-(lpyrryl)-pheny1]-butyric acid is obtained, M.P. l 12-l 13.

Also in an analogous manner [p-(3,4-dimethyl-1-pyrryl)- phenyl]-aceticacid, M.P. l74-l 83 is obtained from 20.2 g of(p-sulphinyliminophenyl)-acetic acid-ethylester, 14 g of 2,3-dimethyl-l,3-butadiene, 0.1 g of hydroquinone and 50 ml of acetonitrile.After recrystallization from methanol, the acid melts at l83-185.

The production of the new starting 2-(p-sulphinyliminophenyl)-butyricacid-ethylester can be carried out in the following manner:

a. A mixture of 7.5 ml of thionylchloride and 10 ml of benzene is addeddropwise while stirring and cooling with ice at l0-20, to a solution of20.7 g of 2-(4-aminophenyl) butyric acidethylester in ml benzene.Thereupon, the reaction mixture is heated to boiling in 15 minutes underreflux while stirring. The residue which remains after evaporation ofthe solvent under reduced pressure yields, after distillation in highvacuum, 2-( p-sulphinylimino-phenyl)-butyirc acid-ethylester as a yellowoil, B.P. /0.1 Torr. I

In an analogous manner the new starting (p-sulphinyliminophenyl)-aceticacid-ethylester. B.P. ll0/0.1 Torr is produced from 17.9 g of(p-aminophenyl)-acetic acidethylester.

EXAMPLE 14 11.5 g (0.050 mol) of 2-[p-( l-pyrryl)-phenyl]-butyric-acid(cf. Example 1) are refluxed for 4 hours in a solution of 2 ml ofconcentrated sulphuric acid in 65 ml of methanol. The reaction mixtureis then cooled to 0 and poured onto ice water. The crude 2-[p-(l-pyrryl)-phenyl]-butyric acidmethyl-ester which precipitates in crystalform is filtered, washed with ice cold sodium carbonate solution andthen with water and dried in vacuum at room temperature. Afterrecrystallization from methanol it melts at 56-58.

In an analogous manner,-using the same amount of ethanol instead ofmethanol, the crude 2-[p-(l-pyrryl)-phenyl]butyric acid-ethylester isobtained which is purified by distillation in high vacuum; B.P. ll8-l23/0.1 Torr, n,, 1.5502, M.P. 29-3 1.

1f 10.] g (0.05 mol) of ['p-(l-pyrryl)-phenyl]-acetic acid with 65 ml ofmethanol and 2 ml of cone. sulphuric acid are also treated in ananalogous manner, [p-( l-pyrryl)-phenyl]- acetic acid-methylester isobtained, B.P. 120l26/ 0.1 Torr, n 1 .5770, M.P. 4344.

If 10.1 g of [p-(l-pyrryl)-phenyl]-acetic acid with 65 ml ethanol and 2ml conc. sulphuric acid are also treated in an analogous manner, [p-(l-pyrryl)-phenyl]-acetic acid ethylester is obtained, B.P. l29-l31/ 0.2Torr, n,, 1.55 29, MP. 55-56.

Also in an analogous manner, using 10.8 g (0.05 mol) of 2- [p-(l-pyrryl)-phenyl]-propionic acid, 65 ml of methanol and 2 ml ofconcentrated sulphuric acid, the 2-[p-( l-pyrryl)-phenyl]-propionicacid-methylester is obtained, B.P. l23/0.008 Torr, n 1.5680, M.P. 4041.

EXAMPLE 1 5 31.8 g of [p-( 1-pyrryl)-phenyl]-acetic acid (of. Example 2)are dissolved in 200 ml of anhydrous methanol and refluxed for 4 hourswith 6 ml of concentrated sulphuric acid. The solvent is distilled offin vacuum at a temperature of at most 40. The residue is taken up inabout 200 ml of methylene chloride and made alkaline, while cooling withice, with 5-N sodium hydroxide. The organic phase is separated off,washed with water and dried over anhydrous magnesium sulphate. The oilwhich remains after evaporation of the solvent is distilled at highvacuum. The fraction 126138/0.3 Torr solidifies in the cold. "Byrecrystallization from carbon tetrachloride-ligroin.[p-(l-pyrryl)-phenyl]-acetic acid-methylester is obtained as colorlesscrystals, M.P. 43-44.

EXAMPLE 16 methylester as a yellowish oil, 13.1. l48-l50/ l .5 Torr,which 4 begins to crystallize after a short time, After crystallizationfrom carbon tetrachloride-groin, the ester melts at 43-44.

EXAMPLE 17 6.9 g of 2-[p-(1-pyrryl)-phenyl]-butyric acid (cf. Example 1)are dissolved in 20 ml of benzene by warming and mixed with a solutionof 2.7 g of 2-dimethylamino-ethanol in 2 ml of benzene. On rubbing, thesalt crystallizes out. It is filtered off by suction, washed with 5 mlof cold ether and dried. After recrystallization from 30 ml benzene anddrying at room temperature in high vacuum, the2-dimethylaminoethanol-salt of the 2-[p-(l-pyrryl)-phenyl]-butyric acidmetals at 96-100, after sintering at 91.

EXAMPLE 18 1.9 g of methyl-[p-( l-pyrryl)-phenyl]-malonicaciddiethylester, 1.4 g of potassium hydroxide, 5 ml of water and ml ofn-butanol are heated to boiling for 3 hours while stirring. The solventis evaporated off at about 12 Torr and the concentrate is dissolved in30 ml of water. The aqueous solution is extracted with 15 ml of etherand after filtration is brought to a pH l-2 with 2-N hydrochloric acid.The fine, colorless precipitate is filtered by suction and washed withwater. The 2-[p-( l-pyrryl)-phenyl]-propionic acid so obtained melts atl68l69.

Analogously there is obtained 2-[p-(l-pyrryl)-phenyl]-butyric acid, M.P.ll21l3.

The new di-substituted malonic acid-diethylester necessary as startingmaterial is produced as follows:

a. A mixture of 80 g of [p-(1-pyrryl)-phenyl]-acetic acidethylester and280 ml of diethyl carbonate are heated to 80. Between and a solution of10.0 g of sodium in 450 ml of abs. ethanol is quickly added whilestirring. The ethanol is thereupon distilled off from the reactionmixture. By gradually raising the bath temperature to 230 distillationis continued until the vapor temperature reaches 200 ml of diethylcarbonate are now added and distilled off until the vapor temperaturereaches 123. The contents of the flask are cooled in ice and neutralizedwith a mixture of 30 ml of glacial acetic acid and 800 ml ice-water. Themixture is extracted twice, each time with 400 ml of ether, the ethersolution washed with 5 percent potassium bi-carbonate solution, driedover sodium sulphate and concentrated, whereupon the [p-( l-pyrryl)-phenyl]-malonicacid-diethylester crystallizes out. it is filtered off bysuction and washed with 50 ml of a mixture of petroleum ether benzene(2: 1) and dried in vacuum. 88.5 g of the desired ester are obtained aslight beige crystals, M.P. 76-81. After crystallization from methanolthe melting point rises to 80-83.

2.0 g of sodium is dissolved in 80 ml of abs. ethanol. The solution isheated to 50 and mixed with a 50-warm solution of 24.0 g of [p-(l-pyrryl)-phenyl]-malonic aciddiethylester in 60 ml of abs. ethanol. Themixture is stirred for half an hour at 4050,and then dropwise, quicklyadded to 16.0 g of methyl-iodide. Thereupon, the reaction mixture isrefluxed for 4 hours while stirring and thereafter again 16.0 g ofmethyl iodide are added. After further refluxing for 2 hours, thereaction mixture is concentrated under reduced pressure, taken up in 300ml of ether and washed with 40 ml each of 10 percent sodium bisulphitesolution and water. The ether solution is dried over sodium sulphate andevaporated whereupon 11.2 g of a yellow oil remain. This is dissolved in100 ml of water with 6.8 g of potassium hydroxide, refluxed for 2 hours,whereby the monosubstituted malonic acid diethylester (startingmaterial) is hydrolyzed, while the required reaction product remainsunchanged. After cooling, the solution is extracted twice, each timewith 200 ml of ether. The ethereal solution is washed neutral with waterand concentrated.

The oil which remains crystallized spontaneously. By recrystallizationfrom benzene-petroleum ether, methyl-[p-( lpyrryl)-phenyl]-malonic aciddiethyl ester is obtained as colorless crystals, M.P. 57-58.

In an analogous manner by using 17.6 g of ethyl iodide twice the newethyl-[p-( l-pyrryl)-phenyl]-malonic acid diethyl ester is produced. Theoily crude product is purified by distillation, B.P. 215] 0.05 Torr.11,, 1.5415.

EXAMPLE l9 Hydrogen sulphide is introduced into a suspension of 4 g ofsulphur powder in 60 ml of cone. aqueous ammonia solution until thesulphur dissolves. Then a solution of 6.0 g of p-( lpyrrl) acetophenonein 24 ml of dioxane is added and the reaction mixture is heated for 12hours in an autoclave to l50160. The partially crystalline reaction ismass then mixed with 100 ml of 5-N sodium hydroxide and 30 m1 ofisopropanol and refluxed for 14 hours. The reaction mixture is dilutedwith 200 ml of water and the organic solvents are evaporated off underreduced pressure. The remaining aqueous solution is stirred with activecharcoal, filtered through Hyflo (diatomaceous earth) and made acid with2-N hydrochloric acid The [p-(l-pyrryl)-phenyl]-acetic acid obtained ascrystals is dissolved in 2-N sodium carbonate solution, againprecipitated with 2-N hydrochloric acid and recrystallized fromisopropanol, whereupon it melts at 180-182.

EXAMPLE 20 12.1 g of [p-( l-pyrryl)-phenyl]-acetic acid, 27 g ofn-butanol, 120 ml of benzene and 100 mg of p-toluene-sulphonic acid arerefluxed for 14 hours in a water separator. The solution is washed with50 ml of percent sodium carbonate solution, dried over anhydrous sodiumsulphate and concentrated in vacuum. The residual oil crystallizes aftera short time. The crystals are filtered off under suction andrecrystallized from isopropanol-benzene. 7.0 g of[p-(1-pyrryl)-phenyl]-acetic acid-n-butylester are obtained, M.P. 40-41.

EXAMPLE 21 6.0 g of 2-[p-(1-pyrryl)-phenyl]-butyric acid are dissolvedin m1 of 2-N potassium hydroxide, the solution is filtered andconcentrated under reduced pressure. The crystalline residue isrecrystallized from dioxane-isopropanol 10:1). The potassium salt of2-[p-( l-pyrryl)-phenyl]-butyric acid so obtained melts at 255,decomposition from 230.

EXAMPLE 22 5.7 g of [p-( l-pyrryl)-phenyl]-acetic acid are suspended in40 ml of isopropanol. By addition of 8 ml of triethylamino a homogeneoussolution is obtained. This is mixed with 20 ml ether and filtered. Afterthe addition of enough petroleum ether (B.P. 4060) to remove theresulting turbidity, the salt gradually crystallizes out on cooling.After drying for 12 hours at 200 Torr, the triethylammonium salt of the[p-(1-pyrryl)- phenyl]-acetic acid melts at 67-73.

EXAMPLE 23 19.8 g (0.15 mol) of 2,5-dimethoxy-tetrahydrofuran, 27.8 g-

under 0.1 Torr at 164, n 1.5976. lt crystallizes on standing.

(M.P. 68-74) and after recrystallization from cyclohexanebenzene (20:1melts at 75-76. Positive Ehrlich reaction.

The starting material is produced as follows:

46.3 g (0.240 mol) of [p-(acetoamido)-phenyl]-acetic acid [8. GabrielChem. Ber. 15, 834 (1882)]are suspended in a mixture of 100 m1 ofacetone and 108 ml of concentrated hydrochloric acid. While stirringvigorously, a solution of 10.7 g (0.100 mol) of sodium chlorate in 13 mlof water is added dropwise within one hour at -5. The reaction mixtureis brought to 0 and stirred for 15 minutes. 75 ml of cone. hydrochloricacid are then added, the solution is refluxed for 2 hours and evaporatedto dryness on a water-bath (at 100) under 15 Torr. The residue is as faras possible dissolved in 250 ml of l-N hydrochloric acid the undissolvedpart (about 2.9 g) separated off by filtration. The hydrochloric acidsolution is brought to pH 2.4 by the addition of 3-N sodium hydroxide.The precipitate is filtered off, washed with water and dried at 80. 31.0g of (4-amino-3-chlorophenyl)-acetic acid are obtained as a grey-brownpowder. M.P. 133135, which can be further processed directly. Throughrecrystallization from water and then from isopropanol-benzene, a puresubstance is obtained, M.P. l35-137. The position of the chlorine atomcan be determined spectroscopically (NMR).

EXAMPLES 24 5.47 g (0.020 mol) of l-[p-(l-carboxypropyl)-phenyl]-2-pyrrol carboxylic acid are heated in a bath at 200 for about 3 minutesuntil the evolution of carbon dioxide stops. The

resulting clear, red liquid solidifies on cooling. Recrystallizationfrom a mixture of 8 ml of benzene and 8 ml of cyclohexane yields 3.16 gof 2-[p-(l-pyrryl)-phenyl]-butyric acid of M.P. l08-l 10. After furtherrecrystallization from ether the melting point is 1 12l 13.

The dicarboxylic acid necessary as starting material is produced asfollows:

a. 34.6 g (0.193 mol) of 2-(p-amino-phenyl)-butyric acid and 38.0 g(0.200 mol) of2,S-dimethoxy-tetrahydro-Z- furan-carboxylicacid-methylester [N. Clauson-Kaas and F. Limborg, Acta Chem. Scand. 6,551 (1952)]are refluxed for 16 hours in 100 ml of acetic acid. The reaction mixture is then evaporated to dryness in a water-bath at 100 under10 Torr. The residue is heated for 1 hour to 100 in a solution of 24 gof sodium hydroxide in 100 ml of water. After cooling to roomtemperature, 100 ml of water, 250 ml of 3-N hydrochloric acid and 1,200ml of chloroform are added. The mixture is vigorously shaken and thenthe chloroform phase is separated off and dried with 50 g of magnesiumsulphate. The solvent is evaporated off on a water-bath at ultimatelyunder 20 Torr. The brown, crystalline residue is rubbed with 50 ml ofether and the resulting crystal suspension is filtered. The crystals arewashed twice with 25 m1 of ether each time and dried. 32.5 g ofl-[p-(l-carboxypropyl)-phenyl]-2-pyrrol carboxylic acid are obtained asan almost white powder which melts on decarboxalizing at l77-17 9 andshows a positive Ehrlich reaction. It is pure enough for subsequentdecarboxylation. By recrystallizing 10.0 g from 70 ml of acetone 4.8 gof pure substance is obtained,

EXAMPLE 25 7.1 g (0.030 mol) of [3-chloro-4-( l-pyrryl)-phenyl]-aceticacid (cf. Example 23) are reacted with 3.27 g (0.030 mol) ofethyl-bromide analogously to Example 6, whereupon 0.54 g (7 percent ofthe theoretical) of 2-[3-chloro-4-(1-pyrryl)-pheny1]-butyric acid areobtained, M.P. 7880 (last crystallization from cyclohexane). PositiveEhrlich reaction. 7

Also analogously to Example 6, 6.0 g (0.025 mol) of [3-chloro-4-(1-pyrryl)-phenyl]-acetic acid are reacted with 4.53 g (0.032mol) of methyl-iodide. 2-[3-chloro-4-( l-pyrryl)- phenyll-propionic acidis obtained, M.P. 7880. Positive Ehrlich reaction.

EXAMPLE 26 24.3 g (0.10 mol) of 2-[p-(l-pyrryl)-phenyl]-butyric acidmethyl ester (see example 14) are refluxed for 1 hour with 134 ml of1.5-N sodium hydroxide solution (0.20 mol) and 134 ml of ethanol. Thereaction solution is then evaporated in vacuo, the residue dissolved inwater, the aqueous alkaline solution shaken with about m1 of ether, thenfiltered and adjusted to pH 3-4 with about 6-N hydrochloric acid. The

precipitated crystals are filtered off with suction, washed withv waterand dried during 15 hours at 50 and about 0.5 Torr. 2-[p-(1-pyrryl)-phenyl]-butyric acid is thus obtained; M.P. 111-112. Afterrecrystallization from benzene-cyclohexane 1:1 the substance melts at ll2-1 13.

EXAMPLE 27 4.20 g (0.02 mol) of 2-[p-( l-pyrryl)-phenyll-butyronitrileare refluxed for 30 hours in a solution of 5.61 g (0.10 mol) ofpotassium hydroxide in 34 ml of methanol and 6 ml of water. The reactionmixture is evaporated in vacuo, the residue dissolved in water, theaqueous alkaline solution shaken with ether, filtered and adjusted to pH34 with about 6-N hydrochloric acid. The precipitated crystals arefiltered with suction, washed with water and dried for 15 hours at 50and about 0.5 Torr. The 2-[p-( l-pyrryl)-phenyl]-butyric acid obtainedmelts at ll0l 1 1 after recrystallization from benzene-cyclohexane (1:1)at 1 12-l 13.

In an analogous manner 4.56 g (0.02 mol) of2-[p-(1-pyrryl)-phenyl]-butyramide are hydrolyzed to 2-[p-( l-pyrryl)-phenyl]-butyric acid.

The new starting materials are produced as follows:

a. 18.2 g (0.10 mol) of [p-(l-pyrryl)-phenyl]-acetonitrile are reactedwith 10.9 g (0.10 mol) of ethylbromide analogously to Example 6, toobtain a mixture (about 20 g) of 2-[p-( l-pyrryl)-phenyl]-butyronitrileand 2-ethyl-2- [p-( l-pyrryl)-phenyl]-butyronitrile the pure substancesof which are isolated by preparative thin layer chromatography. The2-[p-(l-pyrryl)-phenyl]-butyronitrole obtained melts at 3839.

a 12.2 g (0.50 mol) of 2-[p-(1-pyrryl)-phenyl]-butyric acid methyl ester(see Example 14) are heated for 6 hours at 180 in an autoclave with 30ml of ammonia (measured at 40). The reaction mixture is evaporatedfinally at 50 and 0.1 Torr and the residue is recrystallized from 60 mlof benzene. The 2-[p-( l-pyrryl)-phenyl]-butyramide obtained, M.P.141144, is dissolved in 1,000 ml of ether for further purification, theether solution is filtered, washed with 20 ml l-N hydrochloric acid andthree times with 50 ml each of water and dried over sodium sulphate. Theether solution is concentrated to 50 ml pure 2-[p-(1-pyrryl)-phenyl]-butyramide crystallizing out, M.P. l45l46.

EXAMPLE 28 0.9 of methyl-[p-( l-pyrryl)-phenyl]-malonic acid is heatedfor 20 minutes at 170180 on an oil bath, after which no evolution of gasis observed. On cooling the reaction product crystallizes. It isdissolved in 3 ml of l-N sodium hydroxide solution. The solution isextracted by shaking with 5 ml of. ether and the aqueous phase isbrought to pH 2 3 with 2N hydrochloric acid.2[p-(1-pyrryl)-phenyl]-propionic acid is obtained, M.P. l6l-l68.' Byrecrystallizing from carbontetrachloride-chloroform the melting pointrises to l68-l69.

The new malonic acid derivative used as starting material is prepared asfollows:

a. 1.9 g of methyl-[p-( l-pyrryl)-phenyl]-malonic acid diethylester (seeExample 18b) are dissolved in 30 ml of ethanol and a solution of 0.9 gof potassium hydroxide in 10 ml of water is added thereto. The solutionis again made homogeneous if necessary by the addition of more ethanoland then stored in the dark for 4 days. After evaporating at 12 Torr and30 bath temperature the residue is dissolved in 10 ml of water and thesolution is extracted with 10 ml of ether. The aqueous phase isacidified to pH 2 with 2-N hydrochloric acid while cooling with ice andthe precipitate of methyl-[p-( l-pyrryl)- phenyl]-malonic acid formed isfiltered by suction, washed with 5 ml of water and dried in vacuo. Thecrude acid melts at 130-140 while evolving gas.

EXAMPLE 29 4.95 g of racemic 2-[p-(1-pyrryl)-phenyl]-butyric acid aredissolved in 30 ml of acetone and a solution of 8 g cinchonidin in 25 mlof methanol is added thereto. The methanol'acetone mixture is evaporatedon a water bath, acetone is added, the mixture is again evaporated andthe residue is taken up in 50 ml of hot acetone. On cooling 11 g of amixture precipitates consisting chiefly of the cinchonidin salt of the()-2-[p-( lpyrryl)-phenyl]-butyric acid and a little excess cinchonidin.It is filtered by suction and the cinchonidin salt is againrecrystallized with acetone. To isolate the free acid, 2 g of therecrystallized cinchonidin salt, M.P. 140, are suspended in 50 ml ofwater, then 15 ml of 2-N hydrochloric acid are added, the precipitatedacid is taken up in ether, the etherified solution is washed twice inwater and dried over sodium sulphate and evaporated. The residue isrecrystallized from carbon tetrachloride and ()-2-[p-(l-pyrryl)-phenyl]-butryic acid is obtained, M.P. -132, [0],, -39.9.

The mother liquors of the two crystallizations of the cinchonidin saltmentioned above are combined and evaporated to dryness in vacuo. Theresidue is suspended in 50 ml of l-N hydrochloric acid and shaken with50 ml of ether until the whole is dissolved. The ether phase isseparated, washed with water, dried over sodium sulphate, andevaporated. The residue (2.65 g) is dissolved in 40 ml of hotisopropanol and a hot solution of 1.8 g (+)-a-phenyl ethylamine in 20 mlof isopropanol is added thereto. On cooling 3.2 g of the(+)-a-phenyl)-ethylamine salt of (+)-2-[p-( lpyrryl)-phenyl]-butyricacid crystallizes as colorless needles which melt after recrystallizingtwice according to the preceding resolution from ethanol at 148-l50,[01],, 4.40 (c 1, methanol). 1.25g of the salt so obtained are suspendedin 30 ml of water. 10 ml of 2-N hydrochloric acid is added and shakenwith ether until the whole is dissolved. The ether phase is separated,washed twice with water, dried over sodium sulphate and evaporated todryness. The residue is recrystallized with 5 ml of carbon-tetrachlorideto obtain (+)-2-[p-( lpyrryl)-phenyl]-butyric acid, M.P. 130l32, [a],,39.9 (c

= 1, methanol).

What is claimed is: l. A compound of the formula R3 R2 If! N CHAzwherein R represents hydrogen, lower alkyl, lower alkenyl or loweralkinyl, R represents hydrogen, lower alkyl, lower alkoxy or halogen,

R and R independently of each other represent hydrogen or lower alkyl,and

A represents c ano or carbamoyl. 2. A compoun as defined in claim 1which IS [p-( 1-pyrryl)- phenyl]-acetonitrile.

3. A compound as defined in claim 1 which is2-[p-(1-pyrryl)-phenyl]-butyronitrile.

4. A compound as defined in claim 1 which is 2-[p-(l-pyrryl)-phenyl]-butyramide.

2. A compound as defined in claim 1 which is(p-(1-pyrryl)-phenyl)-acetonitrile.
 3. A compound as defined in claim 1which is 2-(p-(1-pyrryl)-phenyl) -butyronitrile.
 4. A compound asdefined in claim 1 which is 2-(p-(1-pyrryl)-phenyl)-butyramide.